Combinatorial Chemistry and Synthesis on Solid Support

Combinatorial Chemistry and Synthesis on Solid Support

Burkhard König University of Regensburg

Outline I.

Solid phase synthesis

1. 2. 3.

Polymers, resins, supports Linkers Analytical techniques Solid phase synthesis protocols and automatization

4.

Peptide Synthesis a) Protecting groups (- CO2H, -NH2, side chain= Special topic: Photoremovable protecting groups b) Coupling methods

5. 6. 7.

Oligonucleotides Sugars Special topic: Immobilization of catalysts

Outline II.

Liquid phase synthesis Polyethylenglycol, Linear Polymers, Isomerization reactions, Metathesis

III.

Polymer supported reagents

IV.

Combinatorial Chemistry

1.

Library synthesis a) in solution, parallel synthesis b) on solid support c) split and combine, one bead one compound Deconvolution and Tagging Dynamic combinatorial Chemistry and virtual libraries

2. 3.

Outline V.

Diversity oriented synthesis (DOS) Principle and examples Molecular complexity

VI.

Complexity Generating Reactions Tandem cycloadditions and rearrangements, radical cascade reactions, transition metal catalyzed reactions, mixed tandem reactions, mulit-component reactions

VII.

Chemical Diversity Building blocks, functional groups, stereochemistry, molecular framework, examples of diversity from biosynthesis

An incomplete list of relevant literature reviews Current Opinion in Chemical Biology (2000) 4, Issue 4 - available online.

Bodanszky, M. (1993). Principles of Peptide Synthesis, 2nd Edition. Springer-Verlag: New York.

Schreiber, S. L. (2000). Science 287, 1964-1968. Szostak, J. W. (1997). Introduction: Combinatorial Chemistry. Chemical Reviews 97, 347-348.

Crowley, J. I., Rapoport, H. (1976). Solid-Phase Organic Synthesis: Novelty or Fundamental Concept Concept.. Accounts of Chemical Research 9, 135 - 144.

Pirrung, M. C. (1997). Spatially Addressable Combinatorial Libraries. Chemical Reviews 97, 473-488.

Fréchet, J. M. (1981). Synthesis and Applications of Organic Polymers As Supports and Protecting Groups. Tetrahedron 37, 663 - 683.

Osborne, S. E., and Ellington, A. D. (1997). Nucleic Acid Selection and the Challenge o off Combinatorial Chemistry. Chemical Reviews 97, 349-370.

Gait, M. J., Ed. (1984). Oligonucleotide Synthesis: A Practical Approach. IRL Press: Washington, D. C.

Nefzi, A., Ostresh, J. M., and Houghten, R. A. (1997). The Current Status of Heterocyclic Combinatorial Libraries. Chemical Reviews 97, 449-472 449-472..

Letsinger, R. L. (1983). Chemical Synthesis of Oligonucleotides: a Simplified Approach. Genetic Engineering 5, 191-207.

Pinilla, C., Appel, J., Blondelle, S., Dooley, C., Dorner, B., Eichler, J., Ostresh, J., and Houghten, R. A. (1995). A Review Of the Utility Of Soluble Peptide Combinatorial Libraries. Biopolymers 37, 37, 221-240.

Leznoff, C. C. (1974). The Use of Insoluble Polymer Supports in Organic Chemical Synthesis. Chemical Society Reviews 3, 65 - 85.

Lam, K. S., Lebl, M., and Krchnak, V. (1997). The ''One-Bead-One-Compound'' Combinatorial Library Method. Chemical Reviews 97, 411-448. Baldwin, J. J., and Henderson, I. (1996). Recent Advanc Advances es In the Generation Of Small-Molecule Combinatorial Libraries - Encoded Split Synthesis and Solid-Phase Synthetic Methodology. Medicinal Research Reviews 16, 391-405. Lowe, G. (1995). Combinatorial Chemistry. Chemistry. Chemical Society Reviews 24, 329-340. Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J. (1995). Combinatorial Synthesis - the Design Of Compound Libraries and Their Application to Drug Discovery. Tetrahedron 51, 8135-8173.

Leznoff, C. C. (1978). The Use of Insoluble Polymer Supports Supports in General Organic Synthesis. Accounts of Chemical Research 11, 327 - 333. Merrifield, B. (1986). Solid Phase Synthesis. Science 232, 341 - 347. (This is a transcript of Merrifield's Nobe Nobell Award address.) Neckers, D. C. (1978). Solid Phase Synthesis. Chemtech, 108 - 116 Overberger, C. G., Sannes, K. N. (1974). Polymeric Reagents in Organic International Edition in English 13, 99 - 104. Synthesis. Angewandte Chemie Internation Patchornik, A., Kraus, M. A. (1975). The Use of Polymeric Reagents in Organic Sythesis. Pure and Applied Chemistry 43, 503 - 526.

Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gordon, E. M. (1994). Applications Of Combinatorial Technologies to Drug Disc overy .1. Discovery Background and Peptide Combinatorial Libraries. Journal Of Medicinal Chemistry 37, 1233-1251. Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A., and Gallop, M. A. (1994). Applicati Applications Of Combinatorial Technologies to Drug Discovery .2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions. Journal Of Medicinal Chemistry 37, 1385-1401.

I. Solid phase synthesis Synthesis on solid (polymer) support

Why should you care about solid-phase synthesis ? Even if it were the case that the only successful solid-phase chemistries ever performed were the synthesis of oligopeptides and oligonucleotides, it would be difficult to overstate their importance. These advances created entire new areas of research, and have served as the underpinning for almost all modern biochemistry and molecular biology.

Two other primary reasons for caring about solid-phase synthesis: Its interesting!

It served as the basis for much of the early efforts in combinatorial chemistry.

A little history of solid-phase synthesis

1960's: Solid-phase peptide and oligonucleotide synthesis get started.

1970's: Continued development of solid-phase peptide and oligo synthesis, including the development of effective apparati for automated synthesis.

1980's: Peptide chemists and biologists get interested in figuring out how to make truly huge numbers of peptides (and screen them for biological activity). This leads to the development of the firs first combinatorial libraries.

1970's: Synthetic organic chemists begin to explore solid-phase organic synthesis. While interesting, no compelling case is made for actually bothering to do organic chemistry on solid support, and by 1980 most efforts have stagnated. 1980's (late): Interest in solid-phase organic synthesis is renewed, in both academia and the pharmaceutical industry. Adaptation of "modern" synthetic reactions to the solid-phase begins.

1990's: Continued improvements in the rate at which potential drug candidates can be screened (high-throughput screening) lead virtually every major pharmaceutical company to delve into the combinatorial combinato synthesis of non-peptide, non-oligonucleotide pharmacophores.

Bruce Merrifield 1984 Nobel Prize in Chemistry Born July 21, 1921

Benefits often associated with solid-phase synthesis

• Minimized Solubility Problems

• Simplified Purification • Improved Reaction Yields • Simplified Manipulation of Small Molar Quantities • Site Isolation

Why Use Solid Phase Synthesis? Purification of compounds bound to the solid support from those in solution is accomplished by simple filtration This allows the use of a large excess of reagents, improving the efficiency of many transformations The solid support can be used to compartmentalize library members, permitting the use of split-pool synthesis

S S S

S

S

S S

S

S

S

S

S

1. Polymers, resins, supports Book Chapters Barany, G., Kempe, M. (1997). The Context of Solid-Phase Synthesis. In: A Practical Guide to Combinatorial Chemistry. Czarnik, A. W., DeWitt, S. H., Eds. (ACS: Washington, D D.. C.) Chapter 3. Früchtel, J. S., Jüng, G. (1996). Polymer Supported Organic Synthesis: A Review. In: Combinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH: New York) Chapter Chapter 2. Novabiochem (2001). The Combinatorial Chemistry Catalog. Rapp, W. E. (1996). PEG Grafted Polystyrene Tentacle Polymers: Physico-Chemical Properties and Application to Chemical Synthesis. Synthesis. In Combinatorial Peptide and Non-Peptide Libraries. Jüng, G., Ed. (VCH: New York) Chapter 16. Rapp, W. E. (1997). Macro Beads as Microreactors: New Solid-Phase Synthesis Methodology. Methodology. In Combinatorial Chemistry. Wilson, S. R.; Czarnick, A. W., Eds. (Wiley&Sons: New York) Chapter 4. Review Articles Critical tical Vaino, A. R. and Janda, K. D. (2000). Solid-Phase Organic Synthesis: A Cri Understanding of the Resin. Journal of Combinatorial Chemistry, 2, 579-596. Guillier,F., Orain, D. and Bradley, M. (2000). Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and Com Combinatorial Chemistry. Chemical Reviews, 100, 2091-2157.

1. Polymers, resins, supports

Typical loading: 1 mmol / g of resin or 200 pm / bead (for 100 μm aminomethylpolystyrene ~ 5 x 106 beads / g)

1.1 g

1.25 g

1.4 g

(9 wt % substrate)

(20 wt % substrate)

(29 wt % substrate)

X

first resin-bound intermediate, MW = 100

Y

second resin-bound intermediate, MW = 250

Z

final resin-bound intermediate, MW = 400

1. Polymers, resins, supports Polystyrene Resins = polystyrene/DVB copolymer (0.5 - 5% cross-linking)

Cheap; excellent chemical stability; good to ca. 110 - 130 °C at 1% DVB; slightly higher at 2% DVB.

= polystyrene/DVB copolymer (8 - 50% cross-linking)

Cheap; excellent chemical stability; remarkable thermal and mechanical stability; very poor swelling characteristics → low loadings. Often called "macroreticulate" resin.

= polystyrene/Kel-F

Polystyrene grafted onto polyethylene film. Improved thermal, mechanical stability, but lower loading.

= PEPS film

1. Polymers, resins, supports Polyamide Resins Very polar resins; excellent swelling in DMF, H2O; essentially no swelling in CH2Cl2.

= Pepsyn polyamide, a copolymer of:

O H N

NH2

H2C

N H

H2C

O

CH2

O O

BocHN

N H

H N CH2 O

= Pepsyn K

Pepsin occluded in keiselguhr (silica) matrix. Excellent longevity; used in continuous flow SPPS.

1. Polymers, resins, supports Polyamide resins (continued) = Sparrow amide resin, a copolymer of: CH3 N H2C

H N

CH3

H N

H2C

O

H2N

CH2 O

CH2

O

= Polyhipe, a copolymer of the following in a macroreticulate polystyrene/DVB matrix CH3 N H2C

CH3

CH3 N

OCH3

H2C

O

O

O

1. Polymers, resins, supports Poly(ethylene glycol) - containing resins = PEG-PS, PEG covalently grafted onto preformed polystyrene/ 1% DVB copolymer

Lower mechanical and thermal stability than polystyrene, but much better solvent spectrum. (Resin swells in anything but hexanes.)

= POE-PS (Tentagel), PEG polymerized onto polystyrene/1% DVB copolymer A couple other resins you might see OH

= Polyethylene pins, with a grafted crown of: n O HO

O

OH

n

O CH3


Cellulose Spot synthesis on paper

Inorganic support materials Controlled pore glass (CPG); oligonucleotide synthesis controlled pore ceramics (CPS); high thermal stabilty


+

2 - 20 mol%

CH3OCH 2Cl SnCl4 Merrifield JACS 1963, 85, 2149.

Cl

Effects of Crosslinking •

Cross-Linking imparts mechanical stability and improved diffusion and swelling properties to the resin

Without cross-linking, each polymer chain can dissolve under thermodynamically favored conditions

Cross-linking can induce some sites of ‘permanent entanglement’ maintaining structural integrity

Introduction of functional groups

Br2, Tl(III) Br

n-BuLi, TMEDA more convenient

n-BuLi better p- vs oregioselectivity Li

Introduction of functional groups

CO2H

SCH3

i. CO 2 ii. H+

CH 3SSCH 3

Li

i. O 2 ii. H –

ClPPh2

PPh2

OH

For leading references on resin preparations, see the review by Fréchet: Tetrahedron 1981, 37, 663.

Structure of resins Schematic representation of a macroporous solid-phase support

Structure of a resin bead...... OH CH2Cl2 CH 2Cl2 OH

CH2Cl2 OH

CH 2Cl2

10 - 200 μm Resin Bead

CH2Cl2

CH2Cl2

HO

Commercially available functional groups grafted onto PS resins CH2Cl2

CH2Cl2

OH

Cl

a few Angstroms

O

NH2

OH

O

Bead Section

Br OH

H

Mesh size

Tentagel PEG-Polystyrene graft polymers

Swelling of Polymer by Solvent ‘Shrunken’ state

‘Swollen’ state : Permeable to solvent and reagent

Swelling properties Swelling properties of resins

Practical Considerations in Choosing a Solid Support • • • •

Mode of attachment and cleavage of materials from the resin (linker) Compatibility of the chemistry planned for the library synthesis The amount of material desired (loading level) Size - affects efficiency of diffusion within the polymer (reaction rates!)

90 μm (TentaGel) 0.75 mmol/ g 350 pmol/ bead Ca. 180 ng/ bead

500 μm (PS) 1.05 mmol/ g 60 nmol/ bead Ca. 30 μg/ bead

200 μm (PS) 1.05 mmol/ g 4 nmol/ bead Ca. 2 μg/ bead

Diffusion Efficiency

2. Linkers • •

•

A linker covalently connects molecules to the solid support, and should provide a means for their chemical attachment and cleavage Stability of the linker affects the scope of the chemistry that can be employed in the library synthesis Many linkers are adapted from protecting group chemistry

Synthetic Steps

X Resin

Attachment

Linker

Resin

Linker

Molecule

Cleavage Resin

Linker

Molecule

Molecule

General structure

Cleavage conditions

Acid-labile benzyl alcohol anchors

Amide linkers

Linkers Benzylic linkers

Acid Labile Linkers • •

Many historically important resins (Merrifield, Wang, Sasrin, Sieber, Rink resins) have linkers that are cleaved under acidic conditions Acidic conditions were intended to prevent racemization of amino acids during solid phase peptide synthesis X

O

X= H, Wang linker:

O

R O

X= OMe, Sasrin linker:

50% TFA

O

HO

O

O N H

Sieber linker:

R

CH2Cl2

O

R O

1-3% TFA CH2Cl2

H2N

R

Linkers Cleavage by nucleophiles

Catch and release

Nucleophile Labile Linkers Kaiser Oxime linker • Advantage: Introduction of diversity in cleavage step

NO2 R1 NH2 N

R

O O

•

R1

H N

R O

Difficulty: Often too reactive for common nucleophilic reaction conditions

Linkers Internal nucleophilic cleavage

Linkers „Traceless“ linkers

Traceless Linkers •

This type of linker creates a C-C or a C-H bond at the site of cleavage – C-H bond generation : Si-Ge linker (protonolysis or radical reduction) H

Si

TFA

r.t. NHBn

NHBn

Ellman J. et al. JOC, 1995, 60, 6006.

– C-C bond generation cat. PCy3 Cl Ru Cl PCy3Ph

O S HO

S HO

N

N

Olefin metathesis O

OR

O

O

OR

O

Nicolaou KC et al. ACIEE, 1997, 36, 2097.

Safety-catch linker Kenner’s sulfonamide linker • A “safety-catch” linker can solve the reactivity problem with a two step cleavage • 1) An activation step that is orthogonal to common functional groups • 2) Cleavage of the activated linker under mild conditions

O O O S N R' H

Br

N

dilute BnNH2

O R'

i

Pr2NEt, DMSO

Very stable

O O O S N R'

CN

activation

Ellman J. et al. JACS, 1996, 118, 3055.

cleavage

N H

Bn

Alkylsilyl Linker - Fluoride Labile • • •

Mild cleavage conditions compatible with various functional groups Designed for attachment through an alcohol Compatibile with strong anionic, cationic, oxidative, and reductive conditions Me B

*

Tl(OAc)3

OMe cat. Pd(PPh3)4

*

Br2/ CH2Cl2

1% DVB-CL-PS 500- 560 um

* Me

NaOH, THF, 40 h Br

96 %

98 %

* Me

1.5 eq. NHFmoc

Me Me Me Si O

Me Me Me Si

124 nmol/ bead

127 nmol/ bead

6.0 eq. TfOH 2.0 eq. 2,6-lutidine

HO

Me Me Me Si

OMe

1. HF-pyr. THF 2. TMSOMe

HO

NHFmoc

NHFmoc

114 nmol/ bead

90 %

Ellman J. et al. JOC, 1997, 62, 6102. Foley MA et al. J. Comb. Chem. 2001, 3, 312.

Photo-labile linker • • •

Photolytic conditions can be very mild and selective Dimerization of the support-bound nitroso by-product sometimes hampers further cleavage Aryl nitro group is incompatible with some organometallic chemistry

Me MeO O

O NO2

O

Me R

MeO

O

hν, 350 nm HO

R

+

Krafft GA et al. JACS, 1988, 110, 301.

O

O N O

2. Linkers - overview Linkers Cleaved by Moderate Acid

Linkers Cleaved by Strong Acid

Rink Amide resin (X = NH) Rink Acid resin (X = O)

Merrifield Resin O O

OCH3

O

HF

R

HO

R

H3CO

O

Carbamate resin

X

O

TFA/CH2Cl2

R

HX

O O

N H

R

HF

R

RNH2

PAL resin O O

O

PAM resin O

O

R

N H

O

HF, CF3SO3H HO

N H

OCH3

R

OCH3

Wang resin

BHA resin

R

acid

H2N

O

R O

95% TFA

O

HO H2N

R

O O

N H

R O

O

CF3SO3H

O

moderate

H N

R

R

DHPP resin Thioester resin

O O

S

O R

O

strong acid N H

HS

O

O

O

moderate O

R

R

H3C

CH3 O

X

R

acid

HO

R

2. Linkers - overview Linkers Cleaved by Moderate Acid

Silicon-based Resins

PAB resin

SAL resin (X = NH) SAC resin (X = O) O O

N H

O

O

O

moderate acid HO

R

O

N H

R

O

O

(H3C)3Si

Acid-labile carbamate resin

O

O

O

N H

N H

O

moderate acid or F–

HX

R

Silyl ether resin

R

moderate

O

R

RNH2

acid

R Si

O

R'

moderate acid

(R, R = Ph, iPr)

R'OH

or F–

Dihydropyran resin

Ramage resin O

O

O

O R

ArSO3H

ROH

CH3OH, Δ

Si(CH3)3

N H

O

F– O

R HO

R

O

CHA resin

Pbs resin O O O

N H

O

R

O

H N

N H

m oderate

O

ac id

Si

tBu

O O

O

R

F–

O H2N

O R

HO

R

2. Linkers - overview Linkers Cleaved by Weak Acid

Linkers Cleaved by Base or Nucleophiles

XAL resin (Sieber amide resin)

Weinreb amide resin O

O

O

N H

O

N

O

R'MgCl

R

OCH3

O

N H

O

R'

R

R O

1% TFA

O

CH 2Cl2

H2N

LAH

O

R

H

NPE resin

R

O N H

SASRIN resin

O O

O

O

piperidine

R

HO

NO2

O O

R

O

1% TFA

OCH3

R

CH2Cl2

HO

R

Fm resin

O

R

O

O

piperidine

N H

O

HO

R

Trityl resin (X = H) 2-Chlorotrityl resin (X = Cl)

HMFA resin O

AcOH O O

X

CH2Cl2

HO

O O

R

O

piperidine

N H

R

O

R

HO

R

2. Linkers - overview Photocleavable Linkers

α-Methylphenacyl ester resin

Linkers Cleaved by Base or Nucleophiles

O

O O

Let's not forget Merrifield resin...

R

hν HO

CH3

O X

O

R'OH, base

R

R

O

R'O

R

ONb resin (X = O) Nonb resin (X = NH)

LAH

X = O, S

O

HO

R'

O

N H

hν X NO2

OCH3

O

hν

O

OR O

R

O

O

O S

HX

wet CH 3CN

Holmes resin (X = O, NH)

Finally, a couple derived from early oligo work

N H

R

N H

NH4OH

O

HX X

R

ROH NO2

O

CH3

O

Geysen resin OR

N H

NH4OH

ROH

O

O

NO2

N H

NH O

O

hν wet CH3CN

H2N

R

R

Brown, B. B., Wagner, D. S., and Geysen, H. M. (1995). Molecular Diversity 1, 4-12.

R

2. Linkers - overview "Traceless" Linkers

Kenner's "safety catch" resin

Ellman's resin O

R

O

N H

O O

H3C

strong acid

Si CH3

O S

R

Veber's resin

O

N H

O

i CH2N2

R

ii

HO–

HO

R

SCAL resin O R

strong acid

O Si H3C CH3

or F–

H3C

R

O

O

S

S

CH3

O O

N H

HN

R O

Showalter's resin

O

O

iPr

iPr

(CH3)3SiCl, PPh3 or (EtO)2P(S)SH

Si R

strong acid

R

or F–

TFA H2N

R

DSB resin O

Janda's resin CF3 O O

Bu3SnH, AIBN, Δ N H

O

N H H3C H

O

O

i (CH3)3SiCl, PPh3 HO

ii TFA

R

or Raney Ni, H2 S

R

CH3

R

H3C

S

O

Janda, et al. (1996). Tetrahedron Letters 37, 6491-6494.

3. Analytical techniques Off bead analysis • Cleavage, then use of conventional analytical techniques (e.g. LC, MS, NMR) • Requires high sensitivity and high throughput format Example: LC-UV/ MS

OH OH S HO

O Ph

N Ph

R

Kaiser test On bead analysis 1) Colorimetric methods, Kaiser test

Kaiser test On bead analysis 1) Colorimetric methods, Kaiser test

NMR On bead analysis 2) MAS-NMR ( Magic angle spinning NMR )

Magic angle rotor (left), rotor spinning at the magic angle (right) MAS- NMR spectrum (600 MHz) Si O

O

O

OMe O

O

O

O O

Single bead IR On bead analysis 3) Single-bead FT-IR microspectrometry O

O

H

O

O O

HO

O

DIC, DMAP, DMF

O

O

Beads in IR cell Wavelength (cm-1)

4. Peptide Synthesis

Insulin

Protecting groups for -NH2 Benzoyloxycarbonyl group Carbobenzoxy (Cbo) or Z (Zervas) group Introduction

Protecting groups for -NH2 Benzoyloxycarbonyl group Carbobenzoxy (Cbo) or Z (Zervas) group Cleavage

Protecting groups for -NH2 Tert-Butoxycarbonyl group (Boc) Introduction

Di-tert-butyl-biscarbonate Pyrocarbonate

Protecting groups for -NH2 tert-Butoxycarbonyl group (Boc) Cleavage

TFA

Protecting groups for -NH2 Fluorenyl-9-methoxycarbonyl group (Fmoc) Introduction: Fmoc-Cl, Fmoc-Suc

Cleavage

Protecting groups for -COOH cleavage

All kinds of esters

Protecting groups for -COOH Carboxyl protecting groups which can be activated for coupling

hydrazide carbamate

transform into azide

Protecting groups for side chain functional groups Guanodinium group

Di-acylation or nitration; No perfect protecting group available

Protecting groups for side chain functional groups Imidazole H

Amino protecting groups Protection often necessary to increase solubility. cleavage

Protecting groups for side chain functional groups Thiole Strong nucleophile, easily oxidized – must be protected in peptide synthesis.

cleavage

Protecting groups for side chain functional groups Hydroxy groups

Protection usually not necessary in peptide synthesis. Exceptions: Large excess of amino acid used; solubility reasons

cleavage

Protecting groups for side chain functional groups Indole, thioether

Protection usually not necessary in peptide synthesis. Caution: Alkylation of thioether by carbenium ion possible

Protecting groups for side chain functional groups Amides

Protection usually not necessary in peptide synthesis. Exception: Amides with solubility problems; cyclization as side reaction

Protecting groups for side chain functional groups ϖ-Amino- and carboxy groups

Differentiation between α- and ϖ-functional groups necessary

Protecting groups for side chain functional groups ϖ-Amino- and carboxy groups

Special topic: Photocleavable protecting groups and linkers Norrish-type II: ortho-nitrobenzyl alcohols

C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.

Photocleavable protecting groups Norrish-type II: ortho-nitrobenzyl alcohols


Photocleavable protecting groups Norrish-type II: ortho-nitrobenzyl alcohols

Different reaction pathway if functional group to be protected is linked in β-position C. G. Bochet, J. Chem. Soc., Perkin Trans. 1 2002, 125 - 142.

Photocleavable protecting groups Norrish-type II: ortho-nitrobenzyl alcohols Protecting group for ketones:

Photocleavable protecting groups Norrish-type II: ortho-nitrobenzyl alcohols Array synthesis:

Photocleavable protecting groups Norrish-type II: Phenacyl esters OH R

O

Protection of acids. Fast release trigger for biological stimulants.


Photocleavable protecting groups Norrish-type II: Phenacyl esters

Photolabile linkers and resins

F. Guiller, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 - 2157.

Photocleavable linkers

F. Guiller, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 - 2157.

Current developments

Selective deprotection by light of different wavelength



M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.


Selective deprotection by light of different wavelength M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.


M. Kessler, R. Glatthar, B. Giese, C.G. Bochet, Org. Lett. 2003, 5, 1179 - 1181.

Coupling methods

Azide coupling: No racemization, but very slow

Coupling methods Anhydride and mixed anhydride method

Wrong way !

Coupling methods sym anhydride method

Maximum yield: 50 % !

Coupling methods N-Carboxylic acid anhydride method

1,3-Oxazolidin-2,5-dione

Peptide synthesis in aqueous solution

Repeat steps

Coupling methods Carbodiimide method (DCC, EDC)

DCC in situ active Ester formation with additives

Coupling methods Active esters

Synthesis of cyclic peptides PFP ester ring closure

Coupling methods Active ester: 8-Chinolyl ester as internal base

Coupling methods In situ formation of active esters

Expensive reagents !

Coupling methods Segment coupling – native chemical ligation

Coupling methods Segment coupling – native chemical ligation

Synthesis of interleukin 8 (IL-8)

Solution synthesis of large peptides Sakakibara strategy: Pac = Phenylacyl ester; WSCI = water soluble carbodiimide

Solution synthesis of large peptides Sakakibara strategy: How far can we go?

Purification and characterisation of peptides Typical analytical methods

Solid phase synthesis protocols

Merrifield synthesis

PAM anchor group

PAM anchor

Automated peptide synthesis

Protecting group tactics Boc/Bzl

MBHA = p-methyl benzhydrylamide anchor

Protecting group tactics Fmoc/tBu

Anchor groups in solid phase peptide synthesis cleavage

Racemization during peptide synthesis Enol formation

Racemization during peptide synthesis Oxazolon mechanism

Racemization during peptide synthesis

Coupling reagents

Biochemical peptide synthesis Transformation of mRNA into DNA

Biochemical peptide synthesis

Schematic procedure for preparation of recombinant proteins

Biochemical peptide synthesis Recombinant proteins In medicinal chemistry

5. Oligonucleotides

Nucleotides

Nucleosides

Phosphorylated Nucleosides

Oligonucleotide

DNA double strand – B DNA

DNA double strand – A DNA

Physical parameters of nucleobases

Tautomeres ?

Watson – Crick Basenpairing

C-G

T-A

Reversed Watson – Crick Basepairing

T-A Wooble Basenpairing

Shifted by one position

U-G

Hoogsteen Basenpairing

Watson-Crick hydrogen bond acceptor site

A-T

Oligonucleotide Synthesis Synthesis of nucleosides

A-T

Route A

Route A – Hilbert Johnson reaction

Route A – Hilbert Johnson reaction

Route A – Silyl Hilbert Johnson reaction

Route A – Silyl Hilbert Johnson reaction

reactions at different positions possible

Route A – Silyl Hilbert Johnson reaction (2nd example)

Route B

Route C – assembly of the nuclobase

Route to a non-natural Flavin nucleobase

Route C

Pseudo-Uridine

Wyosine

Stereoselective synthesis of α- and β-nucleosides Selective β-nucleoside synthesis

Stereoselective synthesis of α- and β-nucleosides

β-nucleoside

Stereoselective synthesis of α- and β-nucleosides Selective α-nucleoside synthesis

Synthesis of nucleotides and oligonucleotides Chemistry of phosphoric and phosphinic acid esters

Hydrolysis of phosphoric acid triesters

Hydolysis of phosphoric acid triesters

Synthesis of phosphoric acid esters

Phosphoramidite route

H-Phosphonate route

Automated DNA synthesis

First nucleotide in DNA synthesis

Automated DNA synthesis Each nucleotide addition requires four steps 1. Detritylation 2. Activation and Coupling 3. Capping 4. Oxidation Repeat steps for next nucleotide

Phosphoramidite

Detritylation The dimethoxy-trityl protecting group of the 5´-OH group needs to be removed, so that the next base can be added. Trichloroacetic acid (TCA) is used as reagent for cleavage.

Activation and coupling Protonation activates the leaving group

Activation and coupling

Capping To prevent uncoupled nucleotides from reacting in the next step, which leads to wrong sequence

Oxidation

How far can we go ?

Commercial suppliers DNA synthesis: 100 nanomole scale* Customer's country

Price per base** (no setup fee!)

Shipping and handling

USA

US $ 0.29 per base, no setup fee

From US $ 1.00 to US $ 18.00 (see "S&H")

CAN $ 0.39 per base, no setup fee

From CAN $ 1.00 to CAN $ 18 (see "S&H")

US $ 0.29 per base, no setup fee

Nominal charge, could be as low as US $ 3.00 (see "S&H")

Canada All other countries

*Only customers with accounts in good standing are eligible for this scale. All orders at the 100 nmole scale must be placed using our special order form in Microsoft Excel format, please e-mail us your request. 100 nmole (0.1 micromole) synthesis scale will yield typically 0.040-0.150 micromole (40-150 nmole) final product for a regular size, standard purity oligo. Guaranteed minimum 40 nmole for regular size (up to 25-mer) oligos, standard purity (desalted). For longer oligos, 9 OD260 guaranteed minimum (standard purity). Standard purity includes free desalting. All oligos are quantified and three different units of measure are provided to the customer. The relation between these three units is calculated by a computer, but as an approximation for a 20 base long oligo, 50 nmole equals approx. 10 OD260 units or 300 microgram. **Oligos longer than 35 bases, which are ordered without additional purification, will be supplied with no replacement warranty.

Synthesis of a synthetic gene



Washington Post, July 17, 2002

Synthesis of phosphate monoesters

Pyrophosphates of biological relevance

Synthesis of pyrophosphates

Biochemical methods - The principle of PCR The three major steps: Denaturation at 94°C Annealing at 54°C Extension at 72°C

Biochemical methods - The principle of PCR

Biochemical methods - The principle of PCR

Use of PCR in in vitro random selection SELEX = systematic evolution of ligands by experimental enrichtment DNA strand known sequence random sequence

Use of PCR in in vitro random selection

Aptamere Intramere Ribozyme

Aptamere

Didesoxy DNA sequencing DNA strand to be sequenced template strand, labeled with 32P

reaction vessel with didesoxythymidine-5´-triphosphate

reaction vessel with didesoxycytidine-5´-triphosphate

Didesoxy DNA sequencing Long oligo´s 5´ Yellow = C Green = G Red = T Blue = A

Short oligo´s 3´

Didesoxy DNA sequencing

DNA chips in complex mixture

6. Sugars

Protecting groups in carbohydrate synthesis

Protecting groups in carbohydrate synthesis

Transglycosylation

Transglycosylation OR

OR

Trichloroacetamidate activation

Thermodynamic controlled reaction: α-anomere; anomeric effect

Kinetically controlled reaction: β-anomere R.R. Schmidt, W. Kinzy, Adv, Carbohydr. Chem. Biochem. 1994, 50, 21.

Thioglycosides

Activation of a protected glycoside

Oligosaccharide synthesis Segement synthesis and coupling

Oligosaccharide synthesis

Examples of Solid phase oligosaccharide synthesis Danishefsky's Strategies for SPS of Oligosaccharides - Cartoon Form

HO

O

Danishefsky, et al. (1995). A Strategy for a Convergent Synthesis of N-Linked Glycopeptides on a Solid Support. Science 169, 202 - 204. Olig Danishefsky, et al. (1995). Major Simplifications in Oligosaccharide Syntheses Arising from a Solid-Phase Based Method: An Application to the Synthesis of the Lewis b Antigen. Journal of the American Chemical Society 117, 5712 5719.

O

O O

PO PO

O

PO

PO O PO

PO

O

O O

O

PO

O

PO

O

O PO

O

HO PO

PO

HO PO O

PO

PO

PO

O

O

OP

PO

O

HO

PO

O O

Etc.

PO O

PO

HO PO

O PO

OH

iPr

O

iPr

O

Si

O

Si(iPr)2Cl

iPr

O O

O

CH2Cl2, iPr2NEt DMAP

1) DMDO, DCM

O O

Home-made polystyrene derivative

iPr

Si

OH O

O

O

O O

HO O

O

2) ZnCl2, THF

O O

O

O O HO

Ph

O

O HO O

O

O

O O

iPr

O

H3 C

iPr

Si CH3

O

OH O O

O O

O O O

iPr

Si

ZnCl2, THF

O O

iPr

1) DMDO, DCM

O O

H H

O O

O HO O

Si

iPr

O

O

H3 C

O

CH3

O

O O

O

O O

HO O

iPr

Si

O

O

O O

O

H

O

O

Ph O

O

O

O O

O

iPr

O OBn BnO

OH

O O

O

HO O

BnO

O HO O

O O

O

OBn O

O

iPr

Si

O O

OH BnO

O O

iPr

iPr

2) ZnCl2, THF

O

O

O

O O

H

O HO O

O

O O O

OH O O

O O

H3 C

O

O HO O

O

O

O

Ph

CH3

O OH

ZnCl2, THF

O

O

O O

O HO BnO

OBn O

BnO

Cleaved from resin by treatment with TBAF/AcOH in MeOH

O

O

OBn BnO

An example utilizing thioglycoside donors......... The Monomers

OTBDPS

Solid-Phase Synthesis of a Heptasaccharide Phytoalexin Elicitor Nicolaou, et al. (1997). A General and Highly Efficient Solid Phase Synthesis of Oligosaccharides. Total Synthesis of a Heptasaccharide Phytoalexin Elicitor. Journal of the American Chemical Society 119, 449 - 450. Chemi O

O

O

OH

HO

O O

HO HO

O

O

HO HO

HO

O

OH

HO

HO

O

O

OH O

O

OH

OAc

HO

OTBDPS

O2N

O

BzO BzO

O

OBz

O

O

i. HF•Py, THF

I

OTBDPS BnO HO

O O

NO2 O

i. DMTST, 4AMS, B

O

ii. HF•Py, THF

OBz O

hν, THF AcO AcO AcO

O

BnO O OAc

O O

O

O OBz

OH

NO2

OBz BzO BzO

OTDS

O

OH

OBz

BzO BzO

ii. DMTST, 4AMS, A iii. NEt3, CH2Cl2

O

OBz

O

SPh OAc B

OBz O

O

CsCO3, DMF

O

O

NO2

NO2

> 90% by mass gain

SPh

The Iterative HPE Synthesis

HO

BzO BzO

BzO BzO

C

O

OH

HO

Home-made polystyrene derivative

O

BzO BzO

OAc AcO AcO

OH

OTDS

OTDS

OTBDPS

O

OH

BzO BzO

OH

SPh

OBz

O OH

HO

HO

A

O OBz

AcO AcO

OAc

HO HO

BnO FmocO

OAc

O

O

ii. HF•Py, THF

OBz O

95%

i. DMTST, 4AMS, C

OH BzO BzO

O O OBz BnO O

AcO AcO AcO

OAc

i. DMTST, 4AMS, A O O

O

NO2

OBz

OAc

O

BzO BzO

O

BnO

O O

OBz

O OBz BnO O

i. DMTST, 4AMS, B O O

AcO AcO

O

AcO AcO AcO

OBz

O

O

BnO

O O

OBz

OBz

O

O O OBz BnO O

AcO AcO AcO

BzO BzO

O

BzO BzO

O O

DMTST, 4AMS, B

OBz BnO O

O

O OBz BzO BzO

O

AcO AcO AcO

O

OAc

OBz

NO2

OBz O

BzO BzO

i. hν, THF

protected solid-phase oligosaccharide

O

OBz

95% for two steps ii. NaOCH3, CH3OH iii. H2, Pd, CH3OH

O

2) Strategies Utilizing Support-Bound Acceptors Glycosyl sulfoxides OTr PivO

OH

PivO

PivO

O

O

O

PivO

S PivO

S PivO

O

Ph

Tf2O, DTBMP -78 to -60 oC

OTr PivO O O PivO PivO

1. TFA O

PivO

S

2.

PivO

O

OTr PivO O

OTr

PivO

PivO

O S

PivO O

PivO

O

O O

OAc

PivO

ca. 20% overall from first resin-bound sugar!

O

OAc

O

O

OBz

O

OAc

O

NO2 O

O

OH

OAc

O OBz BzO BzO

OAc

O

BzO BzO

BnO

O O

OAc

OAc

NO2

OBz

OAc

OAc

OBz BnO O

ii. HF•Py, THF

O

ii. Ac2O, NEt3

O

AcO AcO AcO

O

i. hν, THF

O

O

AcO AcO AcO

O

O

BzO BzO

O

BzO BzO

AcO AcO

O

O

OAc

O OBz

O OAc

AcO AcO AcO

OBz

OTBDPS BnO HO

AcO AcO

ii. NEt3, CH2Cl2

Ph

Tf2O, DTBMP -78 to -60 oC

O PivO PivO O PivO

O PivO PivO O PivO

S

> 50 % overall yield PivO > Coupling efficiency believed to exceed 90%; resin cleavage ~70-75%

O

Cleavage from resin achieved with: Hg(OCOCF3)2, water, RT, 5 h

Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953.

Combinatorial Synthesis of a Disaccharide Library

OH

OH HO

AcO

O

O OH

O O

OH

O O

N3SAr O

AcO

S

O

CO2H

HOBt, HBTU, NMP

Ph

OPiv

O PivO PivO

H3C

S

OPiv

O

O

O

SOPh OPiv

O

PivO PivO

H3C

O O

SOPh OPMB

N3

O O

N3SOPh

SOPh H3 C

O

O OPMB O O

O

TfOH, THF, –65 °C

O OPiv

OPiv

PivO

OPiv

O PivO

OPiv

OPiv

PivO

SOPh

O

O PivO

PivO

SOPh PivO

OO

O PivO

O

PivO PivO

O

O PivO PivO

Ph PivO

PivO

SOPh OPiv

O OPiv

O CH 3

O

O

Ph

PivO

O

SOPh PivO

SOPh

O

PivO

H N O

PivO

OPiv O

O

PivO PivO

SOPh

SOPh OPiv

O

OPiv

OPiv O

PivO PivO

SOPh

DMF

PivO

OO

N3

SAr

OPMB

SAr N3

OPiv

PivO

H2NNH2

N3

S

O

O AcO

N PivO 3

O

OPMB O

N3 AcO

O

Ph

SAr

OPMB

H3C

HO

N3 SAr

Glycosyl donors: O

AcO

PEG-PS (Tentagel)

SAr

O

O AcO

O

AcO

NHAc

Ph

NH2

Ph

N3

O

The known antigen for Bauhinia purpurea lectin:

O

O

Ph

O O

O O

OH

OH

Ph

Ph

Kahne, D., et al. (1996). Parallel Synthesis and Screening of a Solid Phase Carbohydrate Library. Science 274, 1520 - 1522.

O

O PivO

i. P(CH 3)3, THF ii. AcCl, NEt3, CH 2Cl2

H N

S

O

Ac2O, iBuCOCl, BuCOCl, PhCOCl, D-Ac-Ala-OH, L-Ac-Ala-OH, MeOCO2Cl

iii. 20% TFA/CH2Cl2 iv. LiOH, THF, CH 3OH

O

N3

Acylation agents:

F COCl

I

COCl

S

COCl

N

O–

CO2H

COCl

N+

CO2H

O2N NO2

OH

OH

OH

OH

O HO

H N

O

O OH

S

O

O

O

O

O

O

O C NCH3

O

O

H2C

O

NHAc

S C NCH3

H3C S Cl

3) Bidirectional Glycosylation Strategy O

BnO

O H N

O

O O

O

BnO

O

CCl3 NH

SEt BnO

Monomers

O H N

O

O

HO BnO

acceptor bound

Generation of a small carbohydrate library........

O

BnO BnO

BnO

O

O

HO BnO

TMSOTf

BnO OMe OH

BnO

SEt

O

BnO

O

O

HO BnO

O

OMe

BnO BnO

O NH

O

O BnO

OH

Couple with each monomer

O

O O

BnO BnO

O

O

O

BnO

OBn H N

O

O BnO

NIS/TMSOTf

SEt

O

O

O O

BnO

products obtained as mixture of anomers

O

1. AcOH/H2O

O

O

THPO BnO

O OBn

BnO

O

O BnO

O BnO

SEt OBn

O O

O

BnO

O

O BnO

BnO

O BnO

OBn

O O BnO

O

O

OMe

OBn

BnO HO

O O O

BnO

OBn

2. H2/Pd

HO OH

HO O

O HO

O

O O HO

Boons and Zhu in "Solid Support Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries," P. Seeburger, ed.; Wiley Interscience, New York, pp. 201-211.

O BnO

OH

O

NaOMe, MeOH

O O BnO

1. NaOMe

O

O O

BnO

NIS/TMSOTf

OBn O

BnO

BnO BnO

OBn

BnO

OMe

6 compounds total

NH

BnO BnO

O

O O

donor bound

OBn

HO BnO BnO

O O O

O O

OH

OMe

Solid-Phase Chemical/Enzymatic Oligosaccharide Synthesis Wong, C.-H., et al. (1994). Solid-Phase Chemical Enzymatic Synthesis of Glycopeptides and Oligosaccharides. Journal of the American Chemical Society 116, 1135 - 1136.

H N

OH

HO

O O Si O

H N

O O Si O

NH2

(Gly)6NHBoc

H HO AcHN

O

O

OH

HO HO

NHAc

O

O

H N

β-1,4-galactosyltransferase

O H N

O O

O

Bn

O

N

55%

O

OH

O

HO

OH

OH

O HO

OH

OH H HO2C

HO AcHN HO

O H N

HO

NHAc

HO

HO 2C

OH

O

N

HO

OH

O OH O

O OH

H3C

O

O OH

HO

N

CMP-NeuAc

O

OH O

O

O

NHBoc

N H

Bn

OH

HO

NH2 O– O P O O

GDP-Fucose

NH NHAc

O

NH

H

HO

α-1,3-fucosyltransferase

>95%

HO AcHN

α-2,3-sialyltransferase

O HO

O OH O

OH O

O OH O

OH O

OH O

HO

O

NHBoc

N H

NH

HO2C

NHBoc

N H

Bn

OH

HO

H

HO

NH NHAc

H N

HO

NH

HO AcHN

OH

O HO

O

O OH O

UDP-Gal

OH O

OH

α-chymotrypsin

O OH O

NHBoc

N H

O

O– O– O O P P O O O

O

O H N

O

NH2

HO

Bn

HO2C

NHBoc

N H

65% O H N

OH OH O

O

HO

controlled-pore glass

H N

O

OH

35% + 20% des-NeuAc +45% starting material

NH NHAc

7. Special topic: Immobilization of catalysts

P

R

HOMOGENEOUS CATALYST

SEPARATION OF CATALYST?

R

P

P

C

P

R

C P

P

PURITY OF PRODUCTS

R

P

EASIER RECYCLING

BIPHASIC SYSTEMS

P R P

P

NON-MISCIBLE LIQUID PHASES

P

R P P

C

P

R

C

P

R

P

NON-MISCIBLE LIQUID PHASES

EASIER RECYCLING

R

P

P R P C

C

PURITY OF PRODUCTS

R

P

P R P

SEPARATION OF CATALYST?

C P

BIPHASIC SYSTEMS

P

• Ionic liquids

P

P

P

• Fluorinated

• Supercritical fluids

R

HOMOGENEOUS CATALYST

• Hydrophobic

R C

• Hydrophylic

SOLID CATALYST

P

R

R

P

P C R

P P

C

P R

IMMOBILIZATION METHODS

STRONG INTERACTION

WEAK INTERACTION *LM

[ML*]

ML*

COVALENT BOND

ADSORPTION

SUPPORT

SUPPORT [ML*] [ML*]

ML*

+

[ML*]

ENTRAPMENT

ELECTROSTATIC INTERACTION

SUPPORT

+

[ML*]

[ML*]

+

[ML*]

TYPES OF SUPPORTS linear polymer

cross-linked polymer

highly cross-linked polymer

inorganic

example

polystyrene (PS)

PS-DVB (0.5-3%)

PS-DVB (>5%)

silica

solubility solvent

soluble dependent

swellable dependent

insoluble independent?

insoluble independent

no

little

potential

potential

difficult

filtration

filtration

filtration

high

high

high

high

mass transport problems separation number of anchoring points

IMMOBILISATION BY COVALENT BOND FORMATION (I) ORGANIC POLYMERS

Grafting

P

X

+

Y

P

C*

Z

C*

L*(C*)

R

R

M

P

X

+

Y

P

L*

Z

L*

Polymerisation P

P

X

Precursor

Ligand synthesis in solid phase

SOLUBLE POLYMER SUPPORTS

HOMOGENEOUS REACTION

ULTRAFILTRATION

SOLUBILIZATION IN A NON-MISCIBLE PHASE

Price of membranes

INSOLUBILIZATION OF THE SUPPORTED CATALYST

CHANGE OF TEMPERATURE

O H2C CH2

1. Anionic polymerisation 2. CO2 3. Me2SBH3

OCOCHN2

(PL)4Rh2 toluene reflux

H(CH2CH2)nCH2OH

O O

Run 1 3 7

CHANGE OF SOLVENT

N H

%yield 58 58 58

COOH O

%ee 98 83 61

RECOVERING BY CENTRIFUGATION AT ROOM TEMPERATURE

N H

COOPE

polymeric ligand (PL)

IMMOBILISATION OF HYDROGENATION CATALYSTS: POLYMERISATION

CH2CH

CH3 CH2C

0,08

CH2CH

NaPPh2

0,92

0,08

CH3 CH2C

[Rh(C2H4)Cl]2

0,92

CATALYST

O

O

O

O

86% e.e. O

O

OH

CH2CH N

CH3 CH2C

0,05

O

O

0,85

O

O

OH

Ph2P

CH3 CH2C

(homog. 81% e.e.) reusable in the absence of air

TEST REACTION

0,10

O

O

O

OH

CH2PPh2

Ph2PCH2

CH2OTs

TsOCH2

Ph2P

O

COOH

O

Ph

NHCOMe

H2

R

MeOH

Ph

COOH NHCOMe

ACA

90% e.e.

IMMOBILISATION OF HYDROGENATION CATALYSTS: GRAFTING

Tentagel (n= 60)

Ph2 P

spacer H N

O

PPh2

N

O

PS

n

O

ACA HYDROGENATION Rh+(cod)BF4

-

MeOH: no reaction EtOH: 90% ee, no reusable Benzene/MeOH: 97% ee,

O

reusable once

PS

TEST REACTION

H N

O COOMe

O

PPh2 +

Ru (cod) PPh2 97% ee (rec. 90% ee)

THF/MeOH

H2

OH COOMe R

EXAMPLES OF GRAFTING ONTO POLYMERS: AMINOALCOHOLS

CHO

OH

N

PS

TEST REACTION

Ph

Me

Me

OH

ZnEt2

S

5-10% cat.

80-89% e.e. (R)

PS N

P

Me

Me

OH

92% e.e. (S)

N

Me

Ph

O OH

PS

N

R2

Merrifield (R1=R2=H): Synthesis in solid phase up to 69% ee Barlos (R1=Ph, R2=o-Cl-Ph): Grafting 94% ee

Ph Ph

HO

R1

96% e.e.

EXAMPLES OF GRAFTING ONTO POLYMERS: Mn(salen)

TEST REACTIONS O

P

O

O

n

O

M-CPBA, NMO

Cl

O

OH

m

P

Ph

NCPS (non-cross-linked PS)

cross-linker in JandaJel O

4% catal. -78ºC-rt

n

MeO-PEG

O

O

N Mn

O

O

MeO

N

OH

styrene

dhnapht

yield

%ee

yield

%ee

MeOPEG

62

57

70

76

NCPS

76

51

69

73

JandaJel

81

51

71

79

Merrifield

61

35

69

78

Me

82

52

75

84

SYNTHESIS OF THE LIGAND IN SOLID PHASE

CHO

N

OH

P

O

NH2

N

N

OH

P

t

Bu

OH

O

P

t

Bu

O

HO

t

t

Bu

But

Bu

TEST REACTION Ph

Ph

O

M-CPBA, NMO

N

N Mn

O O

P

t

Bu

Porous PS

61% ee

Gel-type PS

66% ee

Porous polymethacrylate

91% ee

O

t

Bu

OAc But

POLYMERISATION OF TADDOLS

Ar H

TEST REACTION

Ar

O

O

OH

O

Catalyst in the main chain

N

O

OH

O Ar

COR

Ar 1) styrene/DVB

Ph O O

Ph

i

2) Ti(O Pr)2Cl2

CATALYSTS

OH

OH

Catalyst in the cross-linking points

conv.

endo/exo %ee

Ar=Ph

63

87/13

30

Ar=2-napht

92

87/13

56

30

81/19

6

OTHER CATALYSTS FOR HYDROGEN TRANSFER

O

P

H N

N H

TEST REACTION

NH2 O

Ph

SO2

PrOH

Ph

Ph

OH

i

KOH

Ph

Grafting

NH2

H N

SO2

[Ru(p-cymene)Cl2]2

Ph

Support

method

PS

grafting

88

91

tentagel

grafting

9

55

PS

polym.

23

84

PS

polym.

73

91

Ph Polymerisation

+

conv. %ee

[Ir(cod)Cl]2

IMMOBILISATION BY COVALENT BOND FORMATION (II) INORGANIC SOLIDS

O M

L*

(RO)3Si

L*-M-L

Si(OR)4

O O

Si

L*-M-L

Si

L*

O

O

OH

O

OH

O

Si(OR)4 L-M-L*

L*

O

Grafting (ligand or catalyst)

O L*-M-L O

(RO)3Si

O O

Ligand synthesis in solid phase “Polymerisation” (sol-gel synthesis)

INORGANIC SUPPORTS FOR COVALENT IMMOBILIZATION

SiO2

SILANOL GROUPS

quartz

O O

O O

Si

OH

O

Si

geminal

isolated Si

O

Si OH

O vicinal

OSiMe3

O

• Precipitation (hydrolysis) • Pyrolysis SiCl4 (vapour)

OH

O

O O

Si

O

OH

O

silicaS

OH

"end-capped"

MESOPOROUS CRYSTALLINE SILICAS

• Surface area • Porosity (size and distribution) • Silanol density Surfactant (template)

Control of pore size (25-100 Å, narrow distribution)

GRAFTING THROUGH THE METAL CENTRE

Cl

Cl Et2AlCl + (-)-menthol

Al Et

O

SILICA

Al O

O

TEST REACTION

Enantioselectivity similar to that CHO +

obtained with the analogous in

-50OC

CHO

< 15% cat.

homogeneous phase. (2 equivalents of menthol are

31% ee

needed for better selectivities)

POSSIBILITIES FOR SILICA FUNCTIONALIZATION

O

OH

+ (RO)3Si-R'

OH

O

R' functionalized

group

Alkylation Imine or amide formation

-(CH2)3-NHR NH2

Alkylation Radical addition

-(CH2)3-SH -(CH2)3-X (Cl, Br, I) -(CH2)11-Br

Reaction with amines or alcohols (formation of secondary amines, ethers, ureas, carbamates, sulfonamides)

CH2Cl

O

OR Si

O

-(CH2)3-NCO SO2Cl

Radical addition

-(CH2)n-CH=CH2 (0 ≤ n ≤ 6) -(CH2)2-Ph

Aromatic electrophilic substitution

HYDROGENATION CATALYSTS ON SILICA

Ph2 P

PPh2 H N

(EtO)3Si

a) silica/toluene

O

b) [Rh(cod)2]BF4

O

N PPh2

OEt Si

NHCOCH3

N O

TEST REACTION

Ph

-

PPh2

O

COOMe

Rh+(cod)BF4

H N

H2

S Ph

COOMe

S (m2/g) 310

D loading (nm) (μmol/m2) 14 0.18-0.63

NHCOCH3

370 590 No interactions between cationic species

10 4.4

0.22 0.31

conv (min)

% e.e.

100 (20-30)

91.7-93.5

100 (14-23)

92.1-94.5

99 (26) 99 (90)

92.5 89.3

33 (114)

86.8

Deactivation with small pores (pore blocking?)

DIHYDROXYLATION CATALYSTS ON SILICA

O

O Si O

Si

S

S

OMe

N O

MeO

N

N N

O

O OMe

MeO

+ OsO4

N

N

Loss of Os

MeO O

OMe Si

O

N

O

Problem of toxicity

N O

N

TEST REACTION

N N

N

OH Ph

O O O

N

N

O

Si

Ph

K3[Fe(CN)6]/K2CO3

Ph Ph

t

BuOH/water

OH

OMe

77-88% yield 99% e.e.

MeO

EPOXIDATION CATALYSTS ON SILICA

Synthesis of the ligand in solid phase

TEST REACTION R

Ph

Ph

O MCPBA

R

NMO

Ph

Ph

(-78ºC)

N

N Mn

O Cl

t

O

Bu

R

cat.

time

conv (%)

% e.e.

homog. 45 min

97

84

heterog.

92

89

homog. 45 min

81

43

heterog.

74

56

N

H

Si O

OMe O

MCM-41

Me

4h 4h

IMMOBILIZATION WITH FORMATION OF THE SUPPORT

SILICA

O

O

Si

Si(OEt)3 NH

Low surface area (3-11 m2g-1)

Rh(cod)Cl

H2O

NH

x = 0-3

NH

x Si(OEt)4

Rh(cod)Cl

O

NH O

Si

Si(OEt)3

O O

TEST REACTION O

OH i

PrOH

S

KOH

Npht-COCH3

SILICA

x

time (d)

conv (%)

% e.e.

homog.

5

95

26

0

5

75

58

1

7

60

10

3

8

20

15

3

7

30

98

IMMOBILIZATION BY ELECTROSTATIC INTERACTION

L L* M

+

+

L L*

X-

CATIONIC

L

SOLID

L* M+ L*

X-

+

EXCHANGE L

SOLUTION

SOLID

SOLUTION

H2

CHARGE SITUATION

G+ L M

+

M

H+

+

L* M

L*

L metal

ligand

neutral

TYPES OF INORGANIC SUPPORTS

CLAYS MESOPOROUS CRYSTALLINE SILICAS

~ 10 Å

Pores: 25-100 Å AlO6 octahedra

Interlamellar space

SiO4 tetrahedra

MICROPOROUS ZEOLITES Pores: 4-10 Å Supermicropores by partial destruction of the structure

Isomorphous substitutions: Al

+

+

HYDROTALCITES

T O T

-

[Mg0.75Al0.25(OH)2](CO3)0.125

exchangeable cations

+

octahedral layer

+

-

exchangeable anions

-

+

TYPES OF ORGANIC SUPPORTS

HYBRID MATERIALS POLYMERS

p

Grafted organic groups

m

n

X

(RO)3Si + Silica

SO3Na

1) Grafting 2) Transformation (X SO3Na)

Si O

O

O

SILICA SO3Na

Composites CF2

Variations:

CF2

• Main chain: -(CF2)n• Cross-linking: nature and degree +

• Charged group: -COONa, -NR3

CF2 CF2 SO3H +

Si(OR)4

Silica synthesis

CF2 CF2

CF2 CF2 SO3H

CF2 CF2 SO3H

CF2 CF2 SO3H

nafion-silica nanocomposite

THE EXCHANGE PROCESS

[L*-M]+X- + support

L* + M+X- +

support

Na+

support

Na+

L* +

[L*-M]+

support

+ Na+X-

+ M+ + Na X

• Complex and leaving salt in solution

IMPORTANCE OF SOLVENT

• Possible coordination to M: deplacement of chiral ligand • Compatible with support: swelling

HYDROGENATION WITH CLAY-IMMOBILIZED CATALYSTS

HECTORITE

+

Ph

EtOH NHCOCH3

R N

N

PPh2 Rh(cod)

EFFECT OF SUPPORT

PPh2

COOH

H2

COOH

R

NHCOCH3

R=H 70% e.e. 100% conv (1-6 h) 5 cycles

R = Ph hectorite 49% e.e. nontronite 0% e.e.

Ph

HECTORITE

% e.e. Homog.: Heterog.:

MeOH 15 64

EtOH 32 88

H Me

iPrOH 56 84

NH2 PPh2 Fe

COOBu

COOBu H2

COOBu

COOBu

Rh(cod) PPh2

+ 27.2 A

EFFECT OF SOLVENT AND IMMOBILIZATION

IMMOBILIZATION ON CATIONIC SUPPORTS

HYDROTALCITE AS SUPPORT SO3

SO3

OH

-

OH

H2

100% e.e. P

+ Cl Ru

-

Cl

P

COOMe

COOMe H2

SO3 SO3

48% e.e.

-

-

COOMe

COOMe

Big size of the complex

Exchange on the external surface of the hydrotalcite

Unclear points: • Need for a MgAl hydrotalcite • Possibility of reuse

IMMOBILISATION WITHOUT LIGAND-SUPPORT BOND

• Adsorption on the surface Hydrophylic or hydrophobic interactions Supported liquid phase • Entrapment into the pore system “Ship-in-a-bottle” method Entrapment between polymer chains

IMMOBILIZATION BY ADSORPTION

P

HYDROGEN BOND

CF3 Rh(cod) O

O

O

H

H

H

P O

O

COOCH3

H2

COOCH3

S

NHCOCH3

hexane

NHCOCH3 99% e.e.

O

SILICA

HYDROPHOBIC INTERACTION

SILICA

O t

O 12

PPh2

BuCO N Rh(COD)BF4

O

PPh2

Ph

COOCH3

H2

COOCH3

water

Ph

NHCOCH3

NHCOCH3

93% e.e.

O 12

SUPPORTED LIQUID PHASE

Organic

Glass

Porous catalyst particle

COOH MeO

COOH

H2 MeO (S)-naproxen

Glass SO3Na

H2O SO3Na

P Ru P

2Cl SO3Na

Hydrophilic phase: ethyleneglycol Hydrophobic phase: CHCl3/cyclohexane (1:1) Results: tof 24 h-1, 88% e.e. (r.t.)

SO3Na

H2O

Organic Phase

96% e.e. (3ºC)

ENTRAPMENT INTO ZEOLITES

“ship-in-a-bottle” synthesis

channel

Ligand components are small enough to enter the zeolite channels

Mn2+

(zeolite supercage) CHO R2

OH

H H2N

R1

H

H NH2

H N + N Mn O O

R2 R1

R2 R1

Complex is too large to leave And to be accommodated?

ENTRAPMENT INTO MEMBRANES

cross-linked polysiloxane (membrane form)

Me Me Si O Si Me

Me

P

n +

HMe2SiO

P

Rh(cod)

OSiMe2H Si

"curing"

P

Rh(cod) OTf

P

OSiMe2H OSiMe2H

"SWELLING" OTf

SOLVENT EFFECT

Entrapment of Mn(salen)

H2

O COOCH3

OH COOMe 90-93% e.e.

solvent swelling solubility leaching PhCl 173 21 100 Et2O 240 7 90 acetone 15 90 62 MeOH 2 162 54 heptane 235 0.3 12

CONCLUSIONS

contra

pro

Ligand modification (effect on e.e.)

Versatility COVALENT BOND

Metal leaching (possible )

Ligand retention

Ionic character ELECTROSTATIC

Simplicity

Ligand leaching (possible ) Leaching and solubility

ADSORPTION

Without ligand modification Complex size

ENTRAPMENT

Swelling and leaching

References BOOKS • Chiral Catalyst Immobilization and Recycling; D. E. De Vos, I. F. J. Vankelecom, P. A. Jacobs, Eds.; WileyVCH: Weinheim, 2000. • Comprehensive Asymmetric Catalysis; E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer-Verlag: Berlin-Heidelberg, 1999; chapters 37 and 38. • D. C. Sherrington, P. Hodge. Synthesis and Separations using Functional Polymers; Wiley: New York, 1988. • W. T. Ford. Polymeric Reagents and Catalysts; ACS Symposium Series 308, American Chemical Society: Washington, 1986. • H.-U. Blaser, Tetrahedron: Asymmetry 1991, 3, 843. • S. J. Shuttleworth, S. M. Allin, P. K. Sharma, Synthesis 1997, 1217. • L. Pu, Tetrahedron: Asymmetry 1998, 9, 1457.

REVIEWS

• L. Canali, D. C. Sherrington, Chem. Soc. Rev. 1999, 28, 85. • Y. R. de Miguel, J. Chem. Soc. Perkin Trans. 1 2000, 4213. • S. J. Shuttleworth, S. M. Allin, R. D. Wilson, Synthesis 2000, 1035. • Y. R. de Miguel, E. Brulé, R. G. Margue, J. Chem. Soc. Perkin Trans. 1 2001, 3085. • B. Clapham, T. S. Reger, K. D. Janda, Tetrahedron 2001, 57, 4637.

II. Liquid phase synthesis

Dickerson, Tobin J.; Reed, Neal N.; Janda, Kim D. Chem. Rev. 2002, 102, 3325.

Polyglycerol

Haag, R. et. al. J. Comb. Chem., 2002, 4, 112; Haag, R. Chem. Eur. J., 2001, 7, 327

Soluble Polymers

Janda, K. D. Chem. Rev., 1997, 97, 489-509. Janda, K. D. Chem. Rev., 2002, ASAP.

LPS supported synthesis of Prostaglandins

Janda, K. D. JACS., 1997, 119, 8724-8725.

PEG-Supported Sulfoxide for Swern Oxidations

Harris, J. M, etc. J. Org. Chem., 1998, 63, 2407.

Chemical Tagging

Fluorous Method: A solution phase method

Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769.

Starter Library of Mappicine Analogs

Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769.

Automated High Throughput Purification

www.biotage.com

Wilcox’s Precipitons

Bosanac, T.; Yang, J.; Wilcox, C. S. Angew. Chem. Int. Ed. 2001, 40, 1875-1879. Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194-4195.

ROM Polymerization

1st-G: Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. 2nd-G Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.

Features of Phase Trafficking via ROMP

Impurity Trapping: Chromatography Free Mitsunobu Reaction

Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 2999. Barrett, A. G. M. Chem. Bev. 2002, ASAP.

Synthesis of ROMPgel Activated Esters

Barrett, A. G. M., et. al. Org. Lett. 2000, 2, 261-264.

Acylation of Amines Using ROMPgel Supp. Esters


Polymer supported Tosmic Reagent

NC Barrett, A. G. M., et. al. Org. Lett. 2001, 3, 271-273.

Polymer supported Tosmic Reagent


Sequestration of Excess Amine


Bolm ROM-Polymer Catalyst

Bolm, C.; Dinter, C. L.; Seger, A.; Hocker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731.

Radical Reactions on Soluble ROMP Supports

O

O OR Br

Bu3SnH ZnCl2, Et3B, O2

OR

CH2Cl2, -78oC n

Ph Br

O O

O O

Ph Br

AIBN, PhH 80oC

>90:1 de

n

Bu3Sn

H Ph

O

O

R = O

O H

Ph N

O

Precipitate from tin salts with cold MeOH

Enholm, E. J.; Gallagher, M. E. Org. Lett. 2001, 3, 3397-3399. Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3, 3959-3962.

H

O

O O

O

n

Precipitate from tin salts with cold MeOH

H

Capture-ROMP-Release: Synthesis of Amino Acids

Mukherjee, S.; Poon, K. W. C.; Flynn, D. L; Hanson, P. R., Tetrahedron Lett. 2003, 44, 7187-7190.

III. Polymer supported reagents Reviews on polymer-bound reagents Polymer-supported organic catalysts Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401 Recent advances in asymmetric C-C- and C-heteroatom bond forming reactions using polymer-bound catalysts Bräse, S.; Lauterwasser, F.; Ziegert, R. E. Adv. Synth. Catal. 2003, 345, 869 Whole issue dedicated to polymer-bound reagents Chem. Rev. 2002, 102, No. 10 *New tools and concepts for modern organic synthesis Ley, S. V.; Baxendale, I. R. Nature Reviews: Drug Discovery 2002, 1, 573 Functionalized polymers – emerging versatile tools for solution-phase chemistry and automated parallel synthesis Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem. Int. Ed. Engl. 2001, 40, 650 Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation Ley, S.V. et al. J. Chem. Soc., Perkin Trans. 1 2000, 3815 Solid-supported reagents in organic synthesis Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res. Rev. 1999, 19, 97 Solution-phase chemical library synthesis using polymer-assisted purification techniques Parlow, J. J.; Devraj, R. V.; South, M. S. Curr. Opin. in Chem. Biol. 1999, 3, 320 Functionalized polymers: Recent developments and new applications in synthetic organic chemistry Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1219.

III. Polymer supported reagents

Conventional synthesis Re agent

A

+

A

B

B

Solid phase synthesis Reagent

A

+

B

A B

Synthesis using a solid-supported reagent Re agent

A

+

B

A

B

Different types of polymer-bound reagents

Reagents Scavengers Quenching reagents Capture-and-release reagents

R e age nt pro d uct

sub stra te

Scav eng er + substrates

+

+ product

Scav eng er

product

Capt uri ng rea gen t

Release Capt uri ng rea gen t product

Solid Phase Reagent and Scavenger Resins

Attaching reagents to the solid phase instead of substrates provides similar advantages: - Ease of purification allows the use of excess reagents

Reagent Starting Material

+

Reagent

Filter Clean Product

Product

Excess reagents can be removed by use of a solid phase-bound “scavenger” that reacts with or binds the excess reagent

Excess Reagent Starting Material

+ Reagent

1)

Scavenger

Product 2) Filter

Clean Product + Scavenger Reagent

Advantages Compared to solution phase chemistry

Easy workup / can be automated

Toxic or volatile reagents can be immobilized

Two incompatible reagents can be used at the same time (’wolf and lamb’)

Excess reagent can be used

Advantages

Compared to solid phase chemistry

Easier to develop chemistry Easier to analyze intermediates (solution) Convergent synthesis possible

A

B E

C

D

Disadvantages

Slower reaction in some cases Leaching of metal More expensive

Solid supports

Polystyrene Other organic polymers (polyamides etc.) Soluble polymeric supports (PEG, dendrimers) Silica Zeolites Glass Graphite Cellulose

Polystyrene

Microporous polystyrene (1-4% cross-linked) Macroporous polystyrene (30-50% cross-linked) Hybrids (PS/PEG) O O

OH

n

Soluble polystyrene Plugs of microporous polystyrene

How are the reagents/scavengers attached to the resin?

Covalent binding by: - reaction with a derivatized resin - co-polymerization of the reagent with styrene and divinylbenzene Forming an ion-pair

LiPP h 2 Cl

+

Entrapment, reagent enclosed in a polystyrene network

Functionalized polymer

+

PPh2

N aC N NM e 3 Cl

PPh2

NM e 3 CN

Polymer-Bound Reagents

Reage nt substrate

Some examples: Oxidation Reduction Nucleophilic reactions Carbon-carbon bond formation Amide bond formation

Resin-Supported Reagents

Review: Ley, S. V. et al. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195.

product

Scavenger Resins

Reagents for Oxidation

N M e 3 R uO 4

N OsO4

X O N

Ph 2 Cl P Co PP h 3

O

SiO 2

Cr2O7

NMe3

Cl

C rO 3

2-

SiO2

2

NMe3 IO4

KMnO4

C


OH

C

O

PSP = polymer supported perruthenate KRuO 4 NMe 3 Cl

NMe 3 RuO 4

ultrasound

PSP

H

PSP, O2 toluene

OH

O

> 99%

o

75 - 85 C

H

as above H 15C7

83 %

OH

H 15C7

O

Hinzen, B., Lenz, R., Ley, S. V. Synthesis, 1998, 977

C


OH

C

O

Polymer-bound sulfoxide for Swern oxidation O HO OH

O

O

S

t-BuOOH O

DMAP, DIC

H+

S

O

S O

Ph

O

H OH

sulfoxide

Ph

O

O 71 %

(COCl)2, Et 3N OH

O

as above 82 %

Cole, Stock, Kappel Bioorg. Med. Chem. Lett. 2002, 12, 1791 Liu, Y.; Vederas, J. C. J. Org. Chem. 1996, 61, 7856

C


OH

C

O

Poly(vinylpyridinium dichromate)

n + N

N

N

n

CrO 3 N 2Cr 2 O 7

N

cross-linking agent H PDC

OH

O

98%

OH

O

PDC

93%

Fréchet, J. M. J.; Darling, P.; Farrall, M. J. J. Org. Chem. 1981, 46, 1728


HO C

Dihydroxylation & oxidative cleavage of alkenes L

C

C

O + O

C

C

[OsO 4 ]

OH

N OsO 4 HO

C 8 H 17

C 8 H 17 90%

Me 3 NO Cl N

O

N OsO4 H

H

NaIO4 O

65%

Nagayama, S.; Endo, M.; Kobayashi, S. J. Org. Chem. 1998, 63, 6094 Cainelli, G.; Contento, M.; Manescalchi, F.; Plessi, L. Synthesis 1989, 45

OH C

Reagents for Oxidation C

O

C

Epoxidation O O O CF3 PS or Tentagel

N

O

CO

N

Ru

O N

N

C OOH

O S OOH O

Reagents for Oxidation C

O

C

Epoxidation

Oxon

O

SO4H

80%

SO4H

O

80%

Pande, C. S.; Jain, N. Synth. Commun. 1989, 19, 1271


O n

Epoxidation & oxidation of amines O oxirane 82%

NH2

NO2

oxirane

83%

oxirane N

N

83%

O

Shiney, A.; Rajan, P. K. ; Sreekumar, K. Polymer International 1996, 41, 377

Reagents for Oxidation N

N Mn

Asymmetric epoxidation

O

O Cl O Ph Ph

O

Mn-salen NaOCl, 4-PPNO O 37% (94% ee) 4-PPNO = 4-phenylpyridine-N-oxide

Smith, K.; Liu, H.-C. Chem. Commun. 2002, 886

O

Reagents for Reduction C

O

C

OH

NMe3 (CN)BH3

NMe3 BH4

BH4

BH4 N H2

DMF

NH3

H Pd N

PPh3 BH4

N

Zn(BH4)2


BH4 O N H2

H

O

C

OH

BH4 NH3 OH

MeOH 100%

OH

O NMe3BH4

MeO

NiCl2, MeOH

H N MeO

MeO H N MeO 88%

Epimaritidine

Rajasree, K.; Devaky, K. S. J. Appl. Polym. Sci. 2001, 82, 693; Ley, S. V. Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans 1 1999, 1251


O

C

NH2

Reductive amination

O N +

H

NMe3 BH4

H2N

HN

H

94%

Yoon, N. M.; Kim, E. G.; Son, H. S., Choi, J. Synth. Commun. 1993, 23, 1595

Scavengers can be used to remove excess aldehyde or excess amine: N

NH2

C

O


Br

C

H

Dehalogenation Bu

Bu Sn H

NH2 N

NH2 N

N

N

Br N HO

N

N

SnH

N

HO O H

H

H

OH

H OH

O H

H

H

OH

H OH 87%

Gerlach, M.; Jordens, F.; Kuhn, H.; Neumann, W. P. Peterseim, M J. Org. Chem. 1991, 56, 5971

Applications Reagents for oxidation and reduction O

H NMe3 BH4

Cl Cl

NMe3 RuO4

OH Cl

N

O

N

Cl

N TBDMSO 1)

OH NO2

NMe3 OH CH3NO2

Cl

NO2

NMe2 CH3SO2Cl

N

Cl

O

2) TFA

N

OMs

N

OH

N

NMe3 BH4

Cl

N

CH3SO2Cl

NO2 Cl OMs

N

Cl

Several steps and polymer-bound reagents.

NMe3 BH4

Cl

NO2

N

N

H N

NO2

N Cl

NH2 Epibatidine, purity > 90%

Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc. Perkin Trans. 1 1999, 1253

Amide Formation

O

O +

C R

OH

R'

C

H2N

R

N R' H

O O O N H

O S

O

OH HO

N N

R1

PyBrOP

N H

O S

O

O

R1 R2R3NH

N N

N

N N

P

PF6 Br

N

Pop, I. E.; Deprez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62, 2594

N R3

N

PyBrOP =

R2

R1

’Wolf and Lamb’ O Ph

1)

Ph

Li Ph

O Ph

O Ph

NO2 Me

2)

SO3 NH3NH2

H N N

THF

Ph

Reagents that are incompatible in solution can be used together when bound to a solid phase.

Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1977, 99, 4165; J. Am. Chem. Soc. 1981, 103, 7620

Polymer-bound Nucleophiles C

Nucleophilic substitution

X

C

NMe3 Nu

Nu = OAr, CN, SAr, N3, NaCO3, NCO, SePh, NO2, NCS

Br

NMe3 CN

C N

72%

Gordon, M.; DePamphilis, M. L.; Griffin, C. E. J. Org. Chem. 1963, 28, 698

Nu

Carbon-Carbon Bond Formation Horner-Wadsworth-Emmons

C

O

C

C

O O P EtO EtO

CN +

CN

NMe3 OH

H

Cl

Cl

99% O P EtO EtO

O

O

NMe3 OH

O

+ OEt

OEt

H

93% PASSflow reactor used:

Soledenko, W.; Kunz, U.; Jas, G.; Kirschning, A. Bioorg. Med. Chem. Lett. 2002, 12, 1833.

Metathesis

Cross Metathesis R2

R1

catalyst

R1 +

+ CM R2

Ring Closing Metathesis + RCM

Ring Opening Metathesis Polymerization

R R

[M] R ROMP

[M] R n

Metathesis Catalysts

R1

R1

R2

+

+

R2

Schrock type

Grubbs type

L Cl

R

Ru

Cl L

N Mo RO

L = phosphine or carbene

Ph

OR

Metathesis reactions are often difficult to purify as the catalyst (typical 10 – 20 mol%) contaminates the product.

Metathesis

Mechanism R1 [M ]

CH 2

R2 R1 [M ]

R1

[M ]

R2

R1

[M ] R2 R1

Polymer-Bound Metathesis Catalysts Barrett’s ”boomerang” catalysts PC y 3 +

Ru Ph

Cl

CH 2 Cl 2

Cl

reflux

PC y 3 Cl

Ru

+ Ph

Cl

L

L

L 1 = PCy3 L 2 = IM es

N

P

PCy 3

N

IMes

Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D. C.; Procopiou, P. A. Synlett 2000, 1007

Polymer-Bound Metathesis Catalysts Barrett’s ”boomerang” catalysts

R

PC y 3 Ru

Cl

R

PC y 3

+

Cl

Cl

Ru

Cl

L

L

PC y 3 Ru Ph

Cl Cl

L

Ph

PC y 3 Ru

Cl Cl

L

unstable

R +

Polymer-Bound Metathesis Catalysts Recycling of Barrett’s catalyst PC y 3 Ru C l Cl IM es

C O 2 Et

C O 2 Et

1-octene, PPh 3

C O 2 Et

C O 2 Et

Cycle

1

2

3

4

5

6

% Conversion

100

100

100

88

43

7

More Metathesis Catalysts

O

Blechert Mes

N Cl Cl

N

Mes

Ru PCy3 Ph

Cl Cl

Ru PCy2

PEG O Cl

Ph PCy2

Ru

Cl PC y3

Lamaty

Ph

Grubbs

Enantioselective Olefin Metathesis

tBu

iPr

Hoveyda / Schrock

N

O Mo

iPr

O

tBu

O

O

5 mol% catalyst

H

benzene, R T , 24 h

meso compound

90% conversion, 95% ee

Suzuki Reaction Palladium-catalyzed coupling of an aryl/alkenyl halide with a boronic acid/ester. B

B X

+

Pd-cat.

(RO)2B

A

A

or

or X A

+

(RO)2B

or B B A

or B A

Suzuki Reaction

R2

R1

R1

L2 Pd(0)

X

Mechanism

R

1

L2 Pd R2

R

1

L2 Pd X R'ONa

R'O

B(OR")2

R R2

1

L2 Pd OR'

NaX

B(OR")2

Carbon-Carbon Bond Formation Suzuki coupling C

X

+ (HO)2B

sp2

C

C

PdLn Ph2P [Pd]

PPh2

Cl

Pd(PPh3)4

Pd cat.

sp2

LiPPh2

Pd source:

C

PdCl2

Pd(CH3CN)2Cl2

Jang, S. Tetrahedron Lett. 1997, 38, 1793; Fenger, I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287

Pd(dba)2

Na2PdCl4

Suzuki Coupling C

X

+ (HO)2B

sp2

B(OH)2 +

Br

N

Pd cat.

C

C

C

sp2

{Pd} Na2CO3

N

toluene/water reflux 90 - 95 %

Bu

Br

Hex

+ B

{Pd} NaOEt

Bu Hex

benzene 80 oC

O

84 %

O

Suzuki Coupling: Other Catalysts C

X

+ (HO)2B

sp2

O

Si

Si

Zhang

C

O O PEG

NH S

Pd cat.

sp2

O

HN

C

N H

Uozumi Hayashi

[Pd]

PPh2 Pd Cl

O

Buchwald

Cy2 P [Pd] Pd(OAc)2 or Pd2(dba)2

C

Stille Coupling

Br

O O

+ SnBu

P d cat.

=

O

1) cat. L iC l, N M P P d cat. R

M eO

2) N a O M e

R

3

O

O

Pd O P Ar 2

O

Ar 2 P Pd

Advantages: Tin reagents are toxic – easier to handle if bound to a solid support. Tin byproducts often contaminate product in solution reactions.

The Pauson-Khand Reaction

R1

O Co 2 (CO ) 8

R1

+

R2 R2

The Pauson-Khand Reaction On solid phase

O Co 2 (CO)

O

8

benzene 80 o C , 6 h

O

ester hydrolysis

HO

Schore, N. E.; Najdi, S. D. J. Am. Chem. Soc. 1990, 112, 441

The Pauson-Khand Reaction Mechanism RL

RL Co2(CO)8 RL

RS

- 2 CO

- CO RS

RS

Co(CO)3

Co (CO)2

Co (CO)3 RL

RL

R RS

Co(CO)3 Co(CO)2

alkene insertion

RS

RS

Co(CO)3

reductive elimination RS

R (CO)3Co(CO)3 Co RL -Co2(CO)6

Co(CO)3 O

Co(CO)3 CO insertion CO Co(CO)3

CO

R RL

Co(CO)3

RL

RS

O

O R

R

The Pauson-Khand Reaction Using polymer-bound cobalt carbonyl Ph2 P Co (C O ) 3

Co (C O ) 4

P Ph2

T H F, R T

+

1

PPh2 +

Ph2 P Co (C O ) 3

Co (C O ) 4

2

Co 2 (C O ) 8 1,4-dioxane 75 oC

Ph2 P Co (C O )

3

P Co (C O ) 3 Ph2 3

Comely, A.C.; Gibson, S. E.; Hales, N. J. Chem. Commun. 2000, 305

The Pauson-Khand Reaction

Ph2 P

Using polymer-bound cobalt carbonyl

P Ph2

Co(CO)3 Co(CO)3

3

C O 50 m b ar, 3 T sN

70 o C , T H F, 24 h

O

T sN 61 %

Et O 2 C Et O 2 C

as ab ov e

Et O 2 C O Et O 2 C 49 %

The Pauson-Khand Reaction Using polymer-bound promotors O N+

O

2

O

1

SM e

O H

R

+

Co 2 (C O ) 6

1, T H F, RT

R

or 2, D C E, Δ

R = Ph, tBu, M e 2 (O H)C

H

74 - 99% yield

Kerr, W. J. et al, Chem. Comm. 2000, 1467; 1999, 2551.

References

Reviews on polymer-bound organometallic reagents:

Recent advances in asymmetric C-C and C-heteroatom bond forming reactions using polymer-bound catalysts Bräse, Lauterwasser, Ziegert Adv. Synth. Catal. 2003, 345, 869-929 Preparation of polymer-supported ligands and metal complexes for use in catalysis Leadbeater, Marco Chem. Rev. 2002, 102, 3217-3273 Recoverable catalysts and reagents using recyclable polystyrene-based supports McNamara, Dixon, Bradley Chem. Rev. 2002, 102, 3275-3300 Soluble polymers as scaffolds for recoverable catalysts and reagents Dickerson, Reed, Janda Chem. Rev. 2002, 102, 3325-3344 Functionalized polymers – Emerging versatile tools for solution-phase chemistry and automated parallel synthesis Kirschning, Monenschein, Wittenberg Angew. Chem. Int. Ed. Engl. 2001, 40, 650-579 Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library synthesis Ley et al. J. Chem. Soc., Perkin Trans 1 2000, 3815-4195

Scavengers

+

+ product

substrates

Scav eng er

+

Scav eng er

product

Scavengers

O

O

acidic

S OH

OH CH 3

basic

N

N CH 3

NH2

nucleophilic

N

NH2

NH2 O

electrophilic

N

C

O H

Scavengers Application 1) R1X

HN N

BEMP

NMe2 NH

Cl

1) R2X

HN N

NH2

2)

N R 1

Cl

2)

NH2

R2 N N Cl

N R 1

N BEM P

=

N

P

N N

Xu, W.; Mohan, R.; Morrissey, M. M. Bioorg. Med. Chem. Lett. 1998, 8, 1089

Capture and Release

Capturing reagent Capturing reagent

+ substrates

product + contaminants

Release

product

Capture and Release Tamoxifen library R1

R1

O O B B O O

R2

Pt(PPh3)4

R1

B O O B O O

R1

+

+ regioisomer

R1 R2

2) 30% TFA in CH2Cl2

B O O R3

I Si

N H

R2

X

Pd(dppf)Cl2, base

O

1) R2

R3

R2

R3

R3

R3 + regioisomer

5 x 5 library Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62, 7076

Capture and Release Synthesis of β-amino alcohols

OH

O

O

O Cl

NH 2

O

OH

NaH

Impurities OH

O

O OH NH 2

N H

Capture and Release Synthesis of β-amino alcohols using polymer-bound borane

OH

O

O

1)

O Cl

NH 2

O

NaH

N O

BY 2

2) HBY 2

HCl

HBY2 =

O PEG

BH

O OH

2

Hori, M.; Janda, K. D. J. Org. Chem. 1998, 63, 889

Capture-Release Alkylation Utilizing Resin-Bound Sulfonyl Chloride

Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.; Reitz, A. B. Tetrahedron Lett. 1998, 39, 975-978.

N H

Capture Activation-Release: Solid-Supported DCT for Amide Synthesis

Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355-1357.

An Example of Solid Phase Reagents and Scavengers

An extremely efficient three step reductive amination and triflation is accomplished by the use of solid phase reagents and scavengers OH

MeO

RuO4

HO

HO O

NMe3 MeO

NH2

H

MeO

MeO

BH4

MeO

NMe3

MeO

HO

Tf2O, N

N

MeO

N Tf

MeO

98 % 3 steps

Ley SV et al. J. Chem. Soc. Perkins. Trans. I 1999, 63, 6625.

N H

Application: Sildenafil (Viagra™) Pr OE t O N

H 2N +

O

S O

N

H 2N

N

OH

N

O

1

2 OE t Pr

O N

N

S O

N

HN

N

N O

Sildenafil (Viagra

TM

) Pr =

Baxendale, I. R.; Ley, S. V. Bioorg. Med Chem. Lett. 2000, 10, 1983

Sildenafil, building block 1

1) OH

OEt HN

N O

O

O

EtN(i- Pr) 2

N

S Cl

O

OH

2) Et 2 SO 4

O S O

N

crude 1

OH

Sildenafil, building block 2

O Pr

O

Pr

NH 2 NH Me

N

Br

EtO

NH

H

Pr

NH 2

N

O Et

N

BEMP

O + NM e 3 CN cat. H +

N

O

N

1)

N

2) NH 3 /M eOH

NH 2

Pr

BEMP Pr

O Et

N

CN

M nO 2 NC O

O

H N

Pr

O Et

N

CN

O

NH 2 2

BEM P

N N P N N

=

Sildenafil (Viagra™) OEt OEt O S N O

N

HOBt

O

PyBrOP

OH

N

O S N O

O 2

O N

crude 1

NCO

N N

OEt

OEt

N

O S N O

O NH2 Pr HN

N

N

O S N

EtOH/NaOEt MW 10 min/120 oC

N

O

PyBrOP

=

PF6 Br N P N N

Pr N O

N

HN

Sildenafil

HOBt = N HO

N O

N N

Natural Products via Supported Reagents

Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew. Chem., Int. Ed. 2002, 41, 2194-2197 Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 143-154 Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2001, 1482-1484 Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999, 1253-1255 Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc., Perkin Trans. 1 1999, 1251-1252.

Epothilone

S

For a total synthesis of epothilone using polymer-bound reagents, see:

N

Storer, R. I.; Takemoto, T.; Jackson, P. S.; Ley, S. V. Angew. Chem. Int. Ed. 2003, 42, 2521

H O

O OH

O

O OH